The aim of this prospective randomized controlled study was to evaluate whether pretreatment with a small dose of dezocine could prevent remifentanil-induced cough in general anesthesia induction. Trial design: a prospective, randomized, controlled study.
Trang 1R E S E A R C H A R T I C L E Open Access
A small dose of dezocine suppresses
remifentanil-induced cough in general
anesthesia induction: a prospective,
randomized, controlled study
Rui Ma1†, Yu Wei1†and Zifeng Xu1,2*
Abstract
Background: The aim of this prospective randomized controlled study was to evaluate whether pretreatment with
a small dose of dezocine could prevent remifentanil-induced cough in general anesthesia induction
Trial design: a prospective, randomized, controlled study
Methods: A total of 210 patients receiving elective operative hysteroscopy from December 2018 to April 2019 were enrolled in the present study They were randomly equally separated into dezocine group (n = 105) and control group (n = 105) Patients were intravenously pre-administrated with dezocine 0.03 mg/kg (diluted to 5 mL) or the same volume of normal saline 1 min prior to remifentanil infusion One minute later, intravenous injection of propofol 1.5 mg/kg and cisatracurium 0.1 mg/kg were given to all patients for induction of general anesthesia The counts of coughs occurred during the anesthesia induction period were recorded and the severity of cough was scaled
Results: There were 7 cases of mild cough in dezocine group and 18 cases of mild cough, 12 cases of moderate cough and 4 cases of severe cough in control group The incidence rate of cough was significantly lower and the severity of cough was obviously relieved in dezocine group compared to control group (6.67% vs 32.38%,P < 0.001) The two groups were not significantly different in heart rate and mean arterial pressure before the induction, before and after the intubation, and in operating time and postoperative visual analog scale pain scores
Conclusion: This study recommends the efficacy and safety of a pretreatment with a small dose of dezocine in
reducing remifentanil-induced cough during general anesthesia
Date of registration: Retrospectively registered on 2020/04/18
Keywords: Opioids, Cough, General anesthesia, Dezocine, Remifentanil
© The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the
* Correspondence: ZiFengXu_ipm@163.com
†Rui Ma and Yu Wei contributed equally to this work.
1
Department of Anesthesiology, international Peace Maternal and Child
Health Hospital, School of Medicine, Shanghai Key Laboratory of Embryo
Original Disease, Shanghai Municipal Key Clinical Specialty, Shanghai Jiao
Tong University, Huashan Rd 1961, Shanghai 200030, China
2
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Trang 2Opioids are conventionally used as adjunct drugs for
in-duction of general anesthesia [1] Application of opioids
such as fentanyl [2] and sufentanil [3] often elicits cough
during induction of general anesthesia This adverse
ef-fect may lead to increased intracranial pressure and
in-traocular pressure and is extraordinarily dangerous for
patients with diseases such as cerebral aneurysm, open
eye injury and airway [4] Remifentanil is a fentanyl
con-gener characterized by short onset and short action time,
and has been widely applied for induction of general
anesthesia [5] Remifentanil shows an antitussive effect
on brainstem μ-opioid receptors [6]; however, some
studies reported it also causes coughing just like fentanyl
with a incidence rate varies from 26 to 57% during
gen-eral anesthesia [7–10]
There is a growing interest in suitable agents and
methods to prevent remifentanil-induced cough For
in-stance, Kim et al suggests that elongating injection time
over than 60 s could inhibit remifentanil-cough during
anesthesia in children [7] Limited maximal infusion rate
appears to alleviate remifentanil-induced cough as well
[11] Moreover, there is evidence that pretreatment of
several agents such as dexamethasone [12], ketamine or
their combination [13] and propofol [14] has been
re-ported to be useful for suppressing cough provoked by
remifentanil Dezocine is a mixed agonist-antagonist
opi-oid analgesic [15] It was initially identified as a full
agonist ofκ-receptor and partial agonist/antagonist of
μ-receptor [15] Later study suggested it is aκ-receptor
an-tagonist [15, 16] Increasing studies have demonstrated
that dezocine administration is effective and feasible in
preventing the occurrence of sufentanil-induced cough
during the induction of general anesthesia [17, 18]
Nevertheless, few studies are focused on the effect of
dezocine on remifentanil-induced cough
Our study pretreated the patients undergoing elective
hysteroscopic surgery with a small dose of dezocine
prior to remifentanil infusion with a view to
investigat-ing whether dezocine pretreatment is a reliable strategy
to relieve the incidence and severity of
remifentanil-induced cough This prospective randomized controlled
trial would provide some useful clues for further
devel-opment of anesthesia management
Methods
Study design
This study was approved by the National science and
technology ethics committee (approval number: 2017–
101) and registered in the Chinese Clinical Trial Register
(registration number: ChiCTR2000032035) A total of
210 patients with ASA physical status I-II who received
elective hysteroscopic surgery in our hospital from
De-cember 2018 to April 2019 were enrolled in this study
Exclusion criteria were: known hypersensitivity to the drugs used in this study; body mass index > 30 kg/m2; a history of hypertension; severe arrhythmias; chronic bronchitis, asthma, or other respiratory diseases; in-creased intraocular pressure, intrathoracic pressure or intracranial pressure before surgery Written informed consent was obtained from each participant
The incidence of remifentanil (1.5μg/kg)-induced cough in control group was around 30% in our early study (unpublished) We hypothesized that the incidence rate of cough in dezocine group was lower than 10% Based on α = 0.05 (two-sided) and power = 0.95 (β = 0.05), a medium effect size (Cohen’s f = 0.25), the esti-mated sample size was 104 Taking the dropout into ac-count, the sample size was set at 105 in each group The 210 patients were randomly and equally divided into two groups: dezocine group and control group by a computer-generated allocation program
Anesthesia and monitoring
In brief, all patients of the two groups were fasted for 8
h Peripheral venous access was established using a 20-gauge cannula on the dorsal hand in the operating room Heart rate (HR) and blood pressure were monitored Two minutes prior to induction of general anesthesia, patients of the dezocine group received intravenous infu-sion of dezocine 0.03 mg/kg (diluted to 5 mL), while pa-tients of the control group received an injection of 5 mL normal saline
One minute later, remifentanil 1.5μg/kg (1 mg remi-fentanil diluted with normal saline in a 50 mL syringe; Yichang Humanwell Pharmaceutical Co., LTD, Yichang, Hubei Province, China) was administrated to all patients
of the two groups by a syringe pump at a rate of 600 mL/h, followed by intravenous injection of propofol 1.5 mg/kg and cisatracurium 0.1 mg/kg (Hengrui Pharmacutical Co., LTD, Shanghai, China) 1 min later to induce general anesthesia Endotracheal intubation was then conducted and the patients were ventilated mechanically
HR and mean arterial pressure (MAP) before the anesthesia induction, immediately before and 1 min after intubation were recorded Side effects such as vomiting [19], hypoxemia (SpO2< 90%) [20] or other intended ef-fects during the induction period were also recorded The number of coughs of the two groups was recorded and the severity of cough was defined as follows: mild, 1–2; moderate, 3–4; severe, 5 or more [21, 22] In addition, operative time and visual analog scale (VAS) pain score 30 mins and 60 mins postoperatively were recorded and analyzed as well
Statistical analysis
The primary endpoint was the incidence of cough in dif-ferent groups All statistical analyses were done by SPSS
Trang 3software 22.0 (IBM, Chicago, IL, USA) Categorical data,
such as ASA and incidence of cough were expressed as
number (percentage) and compared between groups by
Chi-square test or Wilcoxon rank-sum test Continuous
data, including age and body weight were expressed as
mean ± standard deviation and compared by Students’ t
test Repeated continuous variables, including HR, MAP
were analyzed by repeated measure ANOVA with
Bon-ferroni correction P < 0.05 was defined as significance
level
Results
Demographic characteristics
Total 210 ASA I and II patients were included in this
study They were randomly assigned to dozocine group
(n = 105) or control group (n = 105) The age range of
patients in dozocine group was 25–73 years and body
weight range was 43–80 kg The age range and body
weight of patients in control group were 22–75 years
and 42–89 kg, respectively There was no significant
dif-ference between the two groups in age (41.99 ± 10.43
years vs 42.61 ± 11.26 years, P = 0.680), body weight
(58.82 ± 7.92 kg vs.59.50 ± 9.93 kg, P = 0.586) and ASA
class (P = 0.644) (Table1)
Hysteroscopic surgery was successful in all patients
Intraoperative oxygen saturation (SpO2) of each patient
was 100% Adverse effects such as nausea and vomiting
were not observed in any patient HR and MAP were
not significantly different between the two groups before
the anesthesia induction, before intubation and 1 min
after intubation (P > 0.05, Table 2) Moreover, both the
two groups had significantly decreased HR and MAP
be-fore intubation and 1 min after intubation compared to
those before the anesthesia induction (P < 0.05, Table2)
Incidence and severity of cough, operating time and VAS pain score
As shown in Table3, mild cough was observed in 7 pa-tients of dozocine group, with an incidence of 6.67% Con-trol group had 34 patients with cough (32.38%), including
18 patients with mild cough, 12 patients with moderate cough and 4 patients with severe cough The patients in dozocine group had a significantly lower incidence of cough and improved severity of cough in comparison with those in control group (P < 0.001) Additionally, there were no significant differences in operating time, 30-min and 60-min postoperative VAS pain scores (P > 0.05, Table4)
Discussion
Our study enrolled a total of 210 patients scheduled for hysteroscopic surgery who were equally randomized into dozocine group and control group Patients in these two groups had similar age and body weight The patients in the dozocine group received a small dose of dezocine prior to remifentanil administration, while patients in control group were given the same volume of normal sa-line A pre-emptive administration of dezocine decreased the incidence of cough from 32.38 to 6.67% and relieved the severity of cough These findings suggest that pre-treatment with dezocine could effectively prohibit remifentanil-induced cough during general anesthesia induction in patients undergoing operative hysteroscopy Hysteroscopy is an established endoscopic surgical procedure in obstetrics and gynecology practice for diag-nosis and management of endometrial problems, with advantages of fewer complications, shorter recovery time and lower costs [23,24] However, pain is the most com-mon complication of hysteroscopy because of several procedures such as cervical dilatation, uterine distension and peritoneal irritation [25] Application of appropriate anesthetic agents for maximal anesthetic effect is a crit-ical issue for hysteroscopy [26] Remifentanil is a short-acting anilidopiperidine opioid with unique pharmacoki-netic characteristics, facilitating fast and efficient anal-gesia It is metabolized by esterases independently of hepatic and renal functions, and was therefore elimi-nated at a more rapid speed than other anilidopiperidine opioids [27] Remifentanil alone or in combination with
Table 1 Demographic characteristics of patients in two groups
Group Control group Dezocine group P
Age (year) 41.99 ± 10.43 42.61 ± 11.26 0.680
Body weight (kg) 58.82 ± 7.92 59.50 ± 9.93 0.586
ASA class (I/II) 78/27 74/31 0.644
Data represent mean ± SD or numbers Difference between groups were
compared by students ’ t test or chi-square test
Table 2 Observations of MAP and HR
Variable Group Before induction 1 min before intubation 1 min after intubation (mmHg) Control group 85.64 ± 8.32 70.26 ± 7.47* 69.79 ± 6.19*
Dezocine group 88.03 ± 14.91 70.06 ± 8.24* 70.07 ± 7.94*
HR (beats/min) Control group 81.77 ± 13.04 60.86 ± 8.04* 60.28 ± 7.81*
Dezocine group 79.58 ± 13.71 60.89 ± 7.55* 60.19 ± 6.69*
Difference between groups at same time point was compared by Student’s t test Difference among different time points in the same group was compared by
Trang 4adjunct agents has been widely utilized for general
anesthesia in hysteroscopy [28] In the present study,
similarly, intravenous infusion of remifentanil 1.5μg/kg
in synergy with propofol 1.5 mg/kg and cisatracurium
0.1 mg/kg 1 min later were used for the induction of
general anesthesia in all patients Cough is often elicited
by remifentanil infusion and is a causative factor of
un-desirable conditions including elevated intracranial,
intra-ocular and intra-abdominal pressure [29] In the
present study, the incidence of remifentanil-induced
cough without any pretreatment was 32.38% (34/105)
Previous studies showed an incidence range of 26–57%
during general anesthesia [7, 9–11] The variance may
be possibly attributed to different doses, effect-site
con-centrations and infusion speeds used in different studies
The exact mechanisms behind opioid-induced cough
remain elusive One possible mechanism is that opioids
cause suppression of central sympathetic outflow and
strengthening of the vagus nerve, thus resulting in cough
[30] Pulmonary chemoreflex mediated by irritant
recep-tors or vagal C-fiber receprecep-tors close to pulmonary
ves-sels, opioid-induced histamine release from lung mast
cells and tracheal smooth muscle constriction may be
responsible for occurrence of cough [31] Control of
opioid-induced cough is of paramount clinical
signifi-cance Dezocine is a mixed agonist-antagonist opioid
and its inhibitory action on opioid-induced cough has
been proved in prior studies [17, 32] In our study, the
incidence of remifentanil-induced cough was 32.38% (18
cases of mild cough, 12 cases of moderate cough and 4
cases of severe cough) in the patients pre-administrated
with normal saline, and was 6.67% (7 cases of mild
cough) in the patients pre-administrated with dezocine
This result revealed that pre-administration of dezocine
was effective in suppressing remifentanil-induced cough
during general anesthesia induction In a previous study,
no patient pretreated with infusion of dezocine 0.1 mg/
kg reports sufentanil-induced cough, in contrast the
control patients had a cough incidence of 31.9% [17] Al-though dezocine 0.1 mg/kg seems to exert a more potent suppressive effect, higher HR and blood pressure are de-tected in the patients receiving a pre-emptive infusion of dezocine compared to the control patients in their study
In the current study, 0.03 mg/kg dezocine, a third of an analgesic dose of dezocine was selected Patients in the dozocine group and the control group were not signifi-cantly different in HR and MAP before the anesthesia induction, prior to intubation and 1 min after intubation, and in operating time, 30-min and 60-min postoperative VAS pain scores These observations indicated that pre-administration of dezocine 0.03 mg/kg does not affect hemodynamics, operating time and postoperative pain of patients Postoperative analgesia demands a larger dose
of dezocine
Dezocine was thought to be aκ opioid receptor agon-ist, but recent data suggest it could be aκ opioid recep-tor antagonist [16] The cough suppression by dezocine may be due toκ receptors antagonism or decreased nor-epinephrine and serotonin reuptake [33] Xu et al spec-ulated that dezocine may reduce fentanyl-induced cough
by antagonizing fentanyl-activated μ receptors via acti-vating κ receptors [34] Our study did not unveil the exact mechanisms underlying the suppression on remifentanil-induced cough by dezocine More in-depth studies are necessary to decipher the exact mechanisms Cough suppressing effect of different doses of dezocine was not explored in the present study These limitations should be addressed in future studies
Conclusion
Our study showed that premedication of a low dose of dezocine was capable of effectively and safely repressing remifentanil-induced cough during general anesthesia in the patients receiving operative hysteroscopy This study offers more insights concerning alternative regimens to prevent remifentanil-induced cough
Abbreviations
HR: Heart rate; MAP: Mean arterial pressure; VAS: Visual analog scale Acknowledgements
Not applicable.
Authors ’ contributions
RM designed the project and wrote the manuscript; YW performed the data analysis; ZX collected the data and revised this paper All authors read and approved the final manuscript.
Table 3 Incidence and severity of cough in two groups
Group N None (N/%) Mild cough
(N/%)
Moderate cough (N/%) Severe cough
(N/%)
Cough (N/%)
P Control group 105 71(67.62%) 18(17.31%) 12(11.43%) 4(3.81%) 34(32.38%) < 0.001 Dezocine group 105 98(93.33%) 7(6.67%) 0 0 7(6.67%)
Table 4 Operative duration and postoperative VAS pain scores
of two groups
Group Operative
time (min)
30-min postoperative VAS pain scores
60-min postoperative VAS pain scores Group C 20.4 ± 3.5 2.83 ± 1.33 3.81 ± 1.12
Group D 19.8 ± 4.3 2.65 ± 0.97 3.79 ± 1.11
Trang 5None.
Availability of data and materials
The datasets used and analyzed in the current study are available from the
corresponding author in response to reasonable requests.
Ethics approval and consent to participate
This study was approved by the National science and technology ethics
committee (approval number: 2017 –101) and registered in the Chinese
Clinical Trial Register (registration number: ChiCTR2000032035) Written
informed consent was obtained from each participant.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 18 May 2020 Accepted: 10 September 2020
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